Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Alexander J. Baker-Williams, Fiza Hashmi, Marek A. Budzyński, Mark R. Woodford, Stephanie Gleicher, Samu V. Himanen, Alan M. Makedon, Derek Friedman, Stephanie Cortes, Sara Namek, William G. Stetler-Stevenson, Gennady Bratslavsky, Alaji Bah, Mehdi Mollapour, Lea Sistonen, Dimitra Bourboulia
Publisher: Cell Press
Publication year: 2019
Journal: Cell Reports
Volume number: 28
Issue number: 7
Start page: 1894
End page: 1906


Abstract

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a “reactivating” mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2.


Keywords

extracellular enzymes, extracellular matrix (ECM), heat shock protein (HSP)

Last updated on 2020-04-04 at 04:50